Category: Fitness

Beyond the Grind: A Blueprint for Accelerated Skill Development

What if more isn’t better? What if your efforts are getting in the way of skill mastery? What are you practicing? Does it build mastery, or just wear you down? If practice makes permanent, are you cementing excellence, or engraining flaws?

What’s the cost of more? In this article, we’ll examine what works, what doesn’t, and how to adapt your routine to master your performance.

What Are You Training For? Define Your Purpose

The most important question every athlete must answer is deceptively simple: What exactly are you training for? Your answer reveals whether you’re settling for general fitness or striving for true performance mastery — the latter being the focus of this article.

Getting in Shape vs. Performance Mastery

Getting in shape — improving general health, building strength and endurance, and reaching peak fitness levels — can be accomplished through countless training methods. Almost any program that challenges your body consistently will yield fitness improvements.

Performance mastery demands more. It requires developing specific skills and applying them under pressure. Here, every element serves competitive excellence.

The performance drills are the conditioning. Not separate conditioning disconnected from skill. Training becomes an integrated system where physiological development happens through skill application, not apart from it.

What Defines Perfect Practice?

Perfect practice makes perfect performance. But what exactly constitutes “perfect practice”?

Perfect practice is characterized by three fundamental qualities:

• Direct Transfer — training that closely mimics the exact skills, movements, technique, timing, and conditions needed, wiring the body and brain for performance

  Takeaway: Train what you use in the way you use it, forget the other stuff.

• Context Integration — applying skills and techniques, new and existing, and established patterns in dynamic practice scenarios that mimic the interactive and unpredictable nature of competition, to develop practical adaptable and effective performance

  Takeaway: Apply your skills in progressively challenging performance situations.

• Strategic Recovery — the proactive and intelligent management of physiological resources to optimize adaptation from training, mitigate fatigue, and enhance readiness for subsequent performance

  Takeaway: Treat recovery as training, not an afterthought.

When these elements align, skill development accelerates dramatically. Athletes progress faster initially and ultimately reach higher performance ceilings because they’re building capabilities directly relevant to their competitive demands. Direct Transfer training prioritizes skill development by allocating training time, focus, and recovery resources to relevant practice, improving the rate and quality of skill acquisition.

Why Do Masters Make It Look So Easy?

Watch Steph Curry sink shots without looking at the rim. See Roger Federer return a 140mph serve with precision. Observe Anderson Silva dodge punches by millimeters, seemingly reading his opponent’s mind.

What you’re witnessing is neurological mastery built on multiple foundations with chunking as a foundational role. Chunking is how your brain transforms separate technical elements into unified actions requiring minimal conscious thought.

The underlying mechanism for building this neurological mastery starts with focused, isolated technique drills that train fundamental neural pathways. Tools like bagwork and padwork are crucial here, allowing for the repeated performance of correct form and efficient movement patterns, which programs “chunks” into the nervous system for correct, efficient execution that can be recalled quickly later on. This repeated activation underpins the development of fluid, automatic movements.

The novice boxer laboriously processes each component: plant feet, rotate hips, extend arm, connect with target. The master accesses these as a single chunk—one fluid motion that automatically adjusts to the opponent’s movement. This neurological efficiency frees cognitive resources for higher-level strategy and perception.

Technique drills, practiced with intent, merge these individual components into one fluid motion that can be recalled and executed as a single unit, or chunk. For instance, a novice boxer focuses on the separate steps of a jab: footwork, guard, shoulder rotation, arm extension, fist rotation, and retraction. Through focused drilling, these individual parts become a single “chunk,” allowing a master to execute the jab with speed and fluidity without conscious thought.

As expertise develops, your brain builds upon chunking to create motor schemas, sophisticated performance templates that adapt instantly to changing conditions. These aren’t rigid instructions but adjustable frameworks, like understanding cooking principles rather than following recipes precisely.

Consider the experienced driver on a mountain road: they don’t calculate steering angles and brake pressure — they feel the road and respond intuitively. Elite athletes similarly navigate competitive chaos with control through instantaneous adjustments they’ve built on comprehensive motor schemas, integrating perception, decision-making, and chunked movement patterns.

Isolated drills develop and hone chunks and schemas, but fall apart if not applied in contextual practice. These patterns must be applied under increasingly realistic conditions to develop them for competitive excellence.

Are You Investing or Squandering Your Recovery Resources?

Your body’s recovery is limited. Adaptation from each session draws on these resources.

Recovery is not just passive time between workouts but, an active process deserving strategic allocation:

• Recovery Prioritization — Focus your training on perfecting the skills needed for performance, prioritizing skill development over less relevant activities.
• Interference Management — Minimize training that drains recovery resources.
• Capacity Enhancement — Speed up your recovery. This includes sleep quality, nutrition, hydration, sauna, Zone 2, red light therapy, foam rolling to promote blood flow and remove waste.

Every training decision represents an investment choice — where will you allocate your limited recovery resources for maximum performance return?

The Performance Gap: Why Gym Warriors Fail in the Ring

The gym hero who vanishes under ring lights isn’t bad luck; it’s an explainable neurological failure of transfer. Bridging the gap from masterful technique training to control under chaotic competition demands a deliberate bridge built on four pillars:

   
1. Decision Pressure: While solo drills build foundational skills, they lack the reactive element of a fight. Smart training bridges this gap by progressively layering decision-making into all modalities: from a pad holder who counters, to visualizing defensive needs on the heavy bag, to reacting to subtle cues in shadowboxing, to live partner reaction drills, culminating in live sparring that demands split-second, consequential choices under increasing pressure.

   

2. Perceptual Triggers: Champions see more than movement; they recognize subtle contextual cues – like weight shifts that telegraph attacks before they launch – and react accordingly. Smart training hones this recognition through drills that incorporate authentic visual and kinesthetic information.

   

3. Psychological Resilience: Ring nerves aren’t overcome by willpower alone. Smart training systematically exposes fighters to audience pressure, consequence (even simulated), and strategic uncertainty to build mental fortitude.

   

4. Environmental Realism: The ring or cage, the crowd, and an uncooperative opponent fundamentally change the fight. Preparation must integrate these realities into training scenarios.

Integrate new techniques immediately in low-pressure sparring. Forge resilience through hard sparring under pressure.

Train in a vacuum, and your skills stay there. The gym hero’s downfall isn’t a mystery: skills aren’t magically transported; they’re forged in the fire of fight-like conditions.

The Path to Mastery: Building Your Blueprint

Here’s how to build an elite combat sports program built on smarter, biologically aligned principles:

1. Technical Excellence Through Contextual Integration

Neural Pathway Activation & Skill Encoding

Focused, isolated technique drills train fundamental neural pathways. Bagwork and padwork allow for the repeated performance of correct form and efficient movement patterns, building conditioning by training technique under fatigue.

Technical development accelerates when initially isolated skills are rapidly integrated into performance contexts. Rather than endlessly drilling techniques in isolation, successful athletes quickly apply new skills in increasingly realistic scenarios.

For example, a basketball player might practice a new shooting technique for 10 minutes, then immediately incorporate it into decision-based drills and small-sided games. This progression creates not just technical proficiency but the ability to execute under the perceptual and decision-making demands of competition.

2. The Conditioning Is the Training

The most effective training approaches recognize that technical practice inherently develops the specific conditioning needed for performance. Boxing combinations naturally train the energy systems required for boxing. Tennis movement patterns directly develop the specific endurance needed for match play.

This integration creates remarkable efficiency:

• Simultaneous skill and conditioning.
• Learning to maintain technique under fatigue — crucial for competition.
• Higher engagement leading to greater training intensity.
• More efficient use of time, focus, and recovery resources in relevant practice.

By structuring technical practice to progressively challenge relevant physiological systems, athletes develop conditioning that directly supports performance excellence.

3. Strategic Complementary Development

While sport-specific training forms the foundation of mastery development, certain complementary approaches may enhance performance, if applied strategically.

• Foundation Strength — Targeted resistance training that develops the fundamental force-producing capabilities underlying sport-specific movements.

  An athletics lab study on well-trained MMA athletes showed improvements in strength, power, and aerobic fitness with competition-oriented high-intensity, low-volume strength training (Kostikiadis et al., 2018). However, the study’s outcomes don’t show direct transfer to MMA performance. Because such training heavily taxes the CNS, it requires careful consideration in the scope of athletics programs.

• Movement Efficiency — Mobility and coordination work that enhances the biomechanical foundations of performance.
• Recovery Enhancement — Practices like Zone 2 cardiovascular training, breath work, and sleep optimization that expand recovery capacity

The key distinction: movement efficiency and recovery enhancement primarily support sport-specific development, strength training requires careful management, as it uses limited recovery resources.

4. Individualized Progression Management

The path to mastery isn’t linear — it requires systematic progression based on individual adaptation responses. Successful athletes continuously assess both performance transfer and recovery status, adjusting training loads and emphases accordingly.

This process demands honest evaluation of two critical questions:

• Is my training directly transferring to performance improvement?
• Am I managing recovery resources effectively?

When these questions guide training decisions, both immediate progress and long-term development accelerate.

Why Generalized Training Misses the Mark

You’ve probably seen athletes running through ladders and cones, drills that look fast and agile. These SAQ drills improve fundamental speed, agility, and quickness, especially in developing athletes. However, they don’t develop sport-specific skills, which are best developed and applied as integral components of performance, not isolated drills with low transfer.

Instead, speed, agility, and quickness should be practiced as drills with direct transfer. This involves repeatedly practicing correct performance with integrated footwork to develop sport-specific speed and agility, and using partner-based reaction drills to develop the quickness of relevant skills.

Furthermore, SAQ drills consume finite recovery resources that are better allocated to practicing sport-specific training, which yields greater transfer to performance.

Illustrating the Principles: Integrated Training in Action

Hypothetical Scenario: Elite Combat Sports Program

Imagine a professional MMA team that restructures its training entirely around sport-specific skill development, thoughtfully considering biological rhythms and recovery.

Instead of separate “conditioning”, physiological challenges are integrated directly into technical and tactical training, with the daily schedule potentially looking like this:

• Mid-Morning: High-focus, high-intensity training for skill acquisition and motor learning, taking advantage of peak cognitive function.
• Nap (Post-Training): A 20–30 minute nap to enhance consolidation, memory, and recovery.
• Evening: A second session focused on physical output, more practice, or additional skills, allowing you to capitalize on physical readiness and motor skill reinforcement.

Evening training can be effective for performance. By this time, muscle temperature and neuromuscular performance are likely to be closer to their daily peak. The key thing is that, if the athlete isn’t overly fatigued from the first session and has benefited from the post-training nap, they can maintain good focus and motivation for the evening session. Furthermore, sleep after evening training will help consolidate the motor skills practiced earlier in the day and provide crucial recovery for both the brain and muscles.

Research to Back It Up:

• Napping and consolidation: Studies show that sleep immediately following training is critical for motor learning. (Reference: Walker, M., et al. (2005) – “Sleep-dependent motor skill learning.”)
• Cognitive sharpness and executive function: Cognitive performance, including decision-making and focus, is generally better mid-morning. (Reference: Schmidt & Lee, Motor Learning and Performance (textbook).)

Practical Application:

Training Window: By training in the mid-morning and following it with a nap, you maximize cognitive resources for motor learning, and then later reinforce motor skills with another round of training.

Recovery and Consolidation: The nap and sleep after the second session allow your body and brain to consolidate what’s been learned, promoting both physical recovery and motor skill retention.

The results of such a biologically aligned and integrated approach: Athletes maintain higher technical quality under fatigue, recover better between sessions, and maintain performance longer in competition. Consequently, competitive success improves compared to traditional approaches.

Real-World Application: The Power of Purposeful Training

Case Study: Youth Tennis Development

A tennis academy abandoned traditional agility ladder and cone drills in favor of movement patterns directly connected to game situations. Rather than practicing footwork in isolation, players developed movement skills through progressively challenging game-based scenarios.

After implementing this approach, players showed significantly faster decision-making, more efficient court movement, and greater resilience in competitive pressure situations. Tournament results reflected these improvements, with players demonstrating particular advantages in extended matches where technical consistency under fatigue became crucial.

Creating Your Mastery Blueprint: An Action Plan

How can you apply these principles to accelerate your development?

1. Clarify your purpose — Define whether you’re training for general fitness or specific performance mastery
2. Examine every training element through the lens of transfer — Ask “How directly does this translate to my competitive performance?”
3. Replace isolated drills with contextual alternatives — Integrate technical elements into realistic performance scenarios
4. Structure practice to simultaneously develop skills and specific conditioning — Design technical sessions that progressively challenge relevant energy systems
5. Prioritize recovery enhancement — Implement practices that expand recovery capacity rather than further depleting it
6. Continuously assess both performance transfer and recovery status — Make data-informed adjustments to optimize development

Neurological Foundations of Athletic Mastery

Athletic excellence is built through specific neurophysiogical adaptations. Understanding these mechanisms reveals why certain training approaches accelerate skill development while others waste precious recovery resources.

Motor Pattern Consolidation

Your brain doesn’t store individual movements — it builds integrated neural networks that link perception, decision, and action. This consolidation process follows distinct phases:

• Cognitive Phase: Conscious attention to movement mechanics requires significant mental bandwidth, limiting performance under pressure
• Associative Phase: Movements become more fluid as neural pathways strengthen, though execution still requires some conscious oversight
• Autonomous Phase: Movements become largely subconscious, freeing mental resources for strategic decisions

This progression explains why isolated drills, far above SAQ drills, still fail in competition — they remain trapped in early development phases without advancing to autonomous execution under realistic conditions.

Contextual Encoding

Your brain encodes skills differently based on the learning environment. Skills acquired in simplified settings lack critical contextual triggers needed during performance. Three key mechanisms explain this:

• State-Dependent Learning: Neural pathways formed under specific conditions activate most efficiently under similar conditions
• Perceptual-Motor Coupling: Your brain creates direct links between environmental cues and appropriate responses
• Attentional Framework Development: Training in realistic contexts builds the ability to focus on relevant cues while filtering distractions

Athletes who train primarily through decontextualized drills develop skills that require conscious translation to performance settings — a process that breaks down under competitive pressure.

Skill Transfer Mechanics

Not all practice transfers equally to performance. Transfer effectiveness depends on three neurological factors:

• Movement Pattern Specificity: Similar neural activation sequences between practice and performance
• Decision-Making Integration: Practice that includes the decision constraints present in competition
• Performance Context Replication: Training environments that mirror competitive demands

This explains why athletes can excel in training yet struggle in competition — different neural pathways are being activated in each environment.

Blueprint for Brain-Optimized Training

To accelerate skill development based on these neurological principles:

1. Minimize Isolated Technique Time: Move quickly from technical instruction to contextual application
2. Implement Decision-Rich Practice: Even basic drills should incorporate relevant decisions
3. Create Progressive Pressure Environments: Systematically introduce competitive elements that trigger performance-specific neural adaptation
4. Train Perception: Explicitly develop recognition of critical environmental cues
5. Practice State Regulation: Train under varying emotional conditions to develop adaptable performance states

Training as your brain encodes and accesses athletic skills transforms every practice minute into direct performance enhancement rather than abstract physical development.

The mastery question “What are you training for?” extends to the neurological level — are you training neural pathways that will activate under competitive conditions, or merely developing capabilities that remain inaccessible when they matter most?

The Path Forward: Excellence Through Purposeful Specificity

The science is clear: training that incorporates contextual elements and proper motor learning principles produces superior results at all levels of athletic ability. The path to mastery requires training with precise purpose — where every element directly contributes to performance excellence.

This doesn’t invalidate all general physical development, particularly for beginners or in rehabilitation contexts. However, as performance goals become more defined, training must become increasingly specific to those demands.

By understanding the science of motor learning, training transfer, and recovery management, athletes can create development pathways that maximize both the rate and extent of performance improvement.

The question isn’t whether you can afford to train with greater specificity — it’s whether your ambitions for mastery allow you to train any other way.

References

• Coutts, A.J., et al. (2007). “Monitoring for overreaching in rugby league players.” European Journal of Applied Physiology, 99(3), 313-324.
• Deci, E.L., & Ryan, R.M. (2000). “The ‘what’ and ‘why’ of goal pursuits: Human needs and the self-determination of behavior.” Psychological Inquiry, 11, 227-268.
• El-Ashker, S. (2018). “Cardio-Respiratory Endurance Responses Following a Simulated 3 × 3 Minutes Amateur Boxing Contest in Elite Level Boxers.”
• El-Ashker, S. (2018). “The impact of a boxing training program on physical fitness and technical performance effectiveness.”
• Fathloun, M., et al. (2011). “Effect of specific versus non-specific training on agility performances.” Science & Sports, 26(2), 75-79.
• Gandevia, S.C. (2001). “Spinal and supraspinal factors in human muscle fatigue.” Physiological Reviews, 81(4), 1725-1789.
• Graybiel, A.M. (1998). “The basal ganglia and chunking of action repertoires.” Neurobiology of Learning and Memory, 70(1-2), 119-136.
• Knudson, D. (2005). “Evidence-based practice in kinesiology: The theory to practice gap revisited.” Physical Educator, 62(4), 212-221.
• Kostikiadis, S., et al. (2018). “The Effect of Short-Term Sport-Specific Strength and Conditioning Training on Physical Fitness of Well-Trained Mixed Martial Arts Athletes.” Journal of Sports Science & Medicine, 17(3), 348-358.
• Nader, G.A. (2006). “Concurrent strength and endurance training: From molecules
• Sheppard, J.M., & Young, W.B. (2006). “Agility literature review: Classifications, training and testing.” Journal of Sports Sciences, 24(9), 919-932.
• Smith, A.D. (2003). “Peer relationships in physical activity contexts: A road less traveled in youth sport and exercise psychology research.” Psychology of Sport and Exercise, 4(1), 25-39.
• Wolpert, D.M., et al. (2011). “Principles of sensorimotor learning.” Nature Reviews Neuroscience, 12(12), 739-751.
• Wymbs, N.F., et al. (2012). “Neural evidence that sequence-specific training enhances learning in developmental dyslexia.” Proceedings of the National Academy of Sciences, 109(40), 16731-16736.

We prioritize safety in our workouts, and when it comes to exercises like the seated cable row, that can translate to strict form with limited range of motion. But have you stopped to consider the trade-offs? If these “safe” variations hinder natural movement and don’t improve our ability to function in daily life or sports, do they actually deliver on their promise of preventing injury? And if not, why are we doing them?

Most trainers teach this exercise with rigid posture, fundamentally limiting its functional effectiveness. Instead of instructing clients to remain frozen in place for “safety”, we should encourage more natural biomechanical movement. In practice, coaching this a lot harder than it seems! This article breaks down how it’s done.

Scapular Mechanics: The Key to Effective Movement

The slight forward hinge allows the scapula to protract, creating a more significant stretch on the retractors. This approach:

• Reduces arm dominance
• Strengthens middle trapezius
• Improves rhomboid engagement
• Counteracts rounded shoulder posture

The increased forward reach due to the slight forward hinge allows the scapula to protract, leading to a more significant stretch on the retractors, reducing dominance of the arms, and sets up a more powerful retraction, strengthening the middle trapezius. This strengthens the rhomboids for better posture in sports and daily activities, counteracting the common tendency towards rounded shoulders, as upper cross syndrome.

Planks: Assessing core strength can be challenging, especially when loose clothing or higher body fat levels obscure visual cues. Starting with planks helps them engage their core, while we assess and correct their posture.

Deadlifts: Deadlifts warm up the entire back and posterior chain, training the mechanical hinging of the hip while maintaining a neutral spine, and promoting full back engagement.

Scapular pushups & Pull-ups: These exercises should not be done to failure, but should be to “wake up” the shoulder external rotators, to stimulate neuromuscular engagement.

Detailed Seated Cable Row Execution

Steps to perfect the movement:

Use the neutral close-grip handle to target the lats maximally.

1. Sit tall, chest up, feet planted
2. Tuck chin slightly
3. Engage core and natural lower back curve
4. Push hips back slightly (like a deadlift)
5. Feel the stretch in the lats
6. Pull your elbows back toward your lower ribs, keeping them close to your sides.
7. As you pull, bring your torso upright, lift your chest, retract shoulder blades, and keep shoulders down—core tight, no leaning back
8. Finish with the handle between your navel and solar plexus
9. Squeeze back muscles hard and hold briefly for a peak contraction
10. Keeping chest high, chin neutral, core engaged, control the return

Safety

Rounding places stress on the lumbar discs, risking serious injury. To avoid this, the client must not only have the right cues, but a strong core and good hip and hamstring mobility, as weakness and tightness can contribute to poor form. Follow the ordered approach outlined above, beginning with exercises that engage the core and train hip hinge and mobility, and use scapular protraction and retraction to wake those muscles up.

This approach maximizes the seated cable row’s benefits by improving neuromuscular engagement, muscle recruitment, range of motion, and functional movement patterns, in contrast to overly-cautious “safe” variations that limit natural movement and fluidity and don’t translate well to activities of daily life or athletics.

Hypothesis

High-intensity exercise (HIT) combined with creatine monohydrate supplementation (CM) confers greater neurocognitive benefits than either alone.

Rationale

Combining HIT with CM may enhance creatine’s transport to the brain, leading to greater cognitive, antioxidant, and neuroprotective effects. This is due to creatine’s ability to cross the blood-brain barrier (BBB), potentially increased by exercise-induced blood flow, vasodilation within the brain, and hormonal responses that further stimulate brain creatine uptake. Querido

This mechanistic basis may provide a theoretical framework for enhancing the benefits of other nutraceuticals.

Exercise Brain Benefits

Exercise boosts cerebral blood flow through vasodilation, increased circulatory volume, and enhanced neurovascular coupling, directing blood flow to the brain regions actively engaged in the exercise. High-intensity exercise improves cognitive function and brain health by increasing cerebral blood flow, BDNF, IGF-1, and osteocalcin. S.E. Browne

Creatine Brain Benefits

Creatine supplementation has been shown to improve cognitive function and provide neuroprotection in persons with neurocognitive impairment. J.F. Sandkühler

Creatine supplementation increases brain creatine levels. During stress or trauma, such as intense exercise, creatine supplementation improves oxidative DNA injury and normalizes brain and body creatine levels. S. Forbes

A 2023 review study published in Sports Medicine found long-term high-dosage creatine supplementation increases brain creatine stores, improves cognition and memory, especially in older adults or during times of metabolic stress (e.g. sleep deprivation), improves aspects of recovery from traumatic brain injury in children, and has the potential to reduce symptoms of depression and anxiety. D. Candow

Creatine has shown neuroprotection in PD patients with cognitive decline via creatine transporter uptake. In a rodent model, high-dosage creatine was shown to exert anti-inflammatory, antioxidative, and anti-aggregant effects on α-synucleinopathy. Y. Leem H. Chang

A long-term, multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial for 10g of creatine in PD patients showed benefit to the Unified Parkinson’s Disease Rating Scale (UPDRS) both at 1 year and at 18 months, but eventually terminated early with no determined harm or benefit. K. Kieburtz

To address the nutritional requirements for the demands of the HIT group, each participant will also consume a post-workout protein shake.

Exercise and Cerebral Blood Flow

Aerobic exercise can increase cerebral blood flow and potentially enhance BBB permeability, at least temporarily. For the given volumetric load and intensity of the HIT exercise protocol, cardiovascular output will be high, around 75% HRmax (possibly higher for untrained PD patients, depending on individual motor efficiency). The cardiovascular intensity alone should be sufficient to significantly increase cerebral blood flow and promote physiological adaptations.

High-intensity strength training (HIT) increases IGF-1 levels more significantly compared to cardiovascular training. IGF-1 enhances creatine uptake in muscles, and creatine supplementation further increases IGF-1 mRNA expression in human skeletal muscle, providing a synergistic benefit that supports improved muscle performance and recovery, indirectly benefiting cognitive function through reduced fatigue and better overall physical health.

Due to its high energy requirements, brain cells are susceptible to Reactive Oxygen and Nitrogen Species (RONS), mitochondrial damage, and energy depletion. Strength training produces less RONS due to its reliance on the TCA cycle, resulting in lower ratio of oxidative stress than the amount of cardio required to achieve same cerebral blood flow and hormonal benefits.

Creatine Supplementation Studies

Research indicates that creatine supplementation can improve cognitive function and has neuroprotective effects. However, the dosage and duration required for optimal cognitive benefits are still under investigation.

Combined Effects

Many studies have examined the combined effects of exercise and creatine on muscle performance and recovery, but research on cognitive outcomes is less extensive. The hypothesis that HIT could enhance cerebral creatine uptake is supported by the rationale of increased blood flow and transporter activity.

Enhanced Recovery

Intense exercise and cognitive activity depletes brain phosphocreatine (Pcr) levels. Creatine supplementation can mitigate this depletion and improve recovery from high-intensity exercise, as well as cognitive function. C. Rae, A.C. Passaquin

Decreased Oxidative Stress

CM supplementation decreases oxidative stress by reducing the immediate demand on oxidative phosphorylation (OXPHOS) and its production of RONS, and by directly scavenging free radicals. H. Arazi

Double Crossover Design Overview

Participants: Individuals with early Parkinson’s disease (PD) and mild MDS-UPDRS impairment, randomly selected into groups:

Sequence 1

1. HIT + CM
2. HIT + Placebo
3. CM Only
4. Placebo

Sequence 2

1. HIT + Placebo
2. CM Only
3. Placebo only
4. HIT + CM

Sequence 3

1. CM Only
2. Placebo
3. HIT + CM
4. HIT + Placebo

Sequence 4

1. Placebo
2. HIT + CM
3. HIT + Placebo
4. CM Only

Each participant gets all interventions to control for individual differences, reduce the number of participants needed, and ensure every participant receives an active intervention. Each intervention phase is followed by a 4 week washout period and testing, to monitor possible carryover effects.

Duration: 16 weeks is adequate for observing potential cognitive and neuroprotective effects. Exercise Protocol: High-Intensity Training (HIT): Exercises: Olympic lifts and plyometrics. Frequency & Duration: 70 minutes (including warm-up and cool down), six times per week, supervised to ensure safety, form, and protocol adherence.

For transparency, participants must be fully informed about the potential benefits and risks associated with both the active treatment and the possibility of receiving placebo.

CM Supplementation

Dosage: 10 g of CM daily, split into two 5 g doses (pre- and post-workout), during warm-up and cool-down for HIT group.

Approach for Intensity

Initial Assessment

Assess participants’ current fitness levels, physical condition, and any potential limitations. Develop individualized exercise plans based on the baseline fitness evaluation. Strength Assessment: Calculate 10 RM for deadlift, squat, overhead press, bench press, barbell row, and box jump (height in cm).

For box jump assessment tests, calculate vertical jump, then move to a lower height and gradually increase within a safety threshold to the trainee’s comfort level.

For some bodyweight exercises, it is not possible to directly calculate the 10 RM as for weighted exercises. Instead, use the following formula:

max_reps * intensity * target_reps/10

For example, if the client can do 8 pushups and the desired intensity is 80% of 10 RM for 6 reps, do 8 × 0.8 × 6/10 ≈ 4 pushups. Adjust the number of reps as appropriate to roughly match the desired intensity level.

Progressive Intensity

Begin with 50-60% of maximal 10 repetition effort (10 rm), and increase the intensity 5% every 2-4 weeks, with rest between sets below 60s. Target Intensity Range: Aim to reach and maintain an intensity level of 70-85% of maximal effort for most of the intervention period. This range is typically sufficient to increase blood flow and confer cognitive benefits without excessive risk.

Sessions

• Day 1: HIT + Zone 2 Cardio
• Day 2: Zone 3 Cardio (40 min ergometer)
• Day 3: HIT + Active Recovery
• Day 4: Zone 3 Cardio
• Day 5: HIT + Zone 2 Cardio
• Day 6: Zone 3 Cardio
• Day 7: HIT + Active Recovery

Zone 3 is 30 min of ergometer at 70% HRMax, at the trainee’s convenience.

Zone 2 is 40 min of walking, monitored with a fitness tracker, at the trainee’s convenience.

Active recovery is 10 minutes of walking, monitored with a fitness tracker, followed by a gentle 30 minute group session consisting of a series of instructor-led mobility movements.

Moderate Intensity Exercise (Zone 3) improves increasing cerebral blood flow and cardiovascular health at a reduced injury risk.

Low Intensity Cardio (Zone 2) improves aerobic endurance and promote recovery, ensuring sustained exercise adherence and minimizing injury risk.

Active Recovery promotes recovery, reduces soreness, and promotes relaxation, contributing to program sustainability.

Incorporating moderate or low intensity exercise and active recovery into a high-intensity training (HIT) routine for individuals, especially those with early Parkinson’s disease (PD), can help mitigate the risk of burnout, overtraining, and CNS overstimulation while still promoting various physiological and cognitive benefits. Here’s a proposed routine that balances HIT with cardio and recovery:

Each 70 minute HIT session begins with a 20 minute warm up, followed by 30 minutes of work, and ends with a 20 minute cool down. Warm Up: 15 minutes of working exercises performed at 40–50% of 10 RM for 10 sets of 3-5 and 10 minutes of mobility and light stretching to avoid injury and improve recovery (hang stretch, scapular pushup, cat/cow, walking, box squat, half kneel hip flexor stretch, etc.). Cool down: 10 minutes of low intensity cardiovascular exercise (fast walking) and 10 minutes of stretching.

HIT Progressive Intensity Exercise Protocol

4 times per week, 30 minutes of working sets, 60 – 75s rest between sets for a total of 15 sets.

Weeks 1-4:

Moderate intensity (50-60% of 10 RM) Volume: 15 sets of 10 repetitions

Weeks 5-8

Increase to moderate-high intensity (65-75% of 10 RM) Volume: 15 sets of 8-10 repetitions

Weeks 9-12

Further increase to high intensity (80-90% of 10 RM) Volume: 15 sets of 6-8 repetitions

Weeks 13-16

High-intensity (95-105% of 10 RM) Volume: 15 sets of 3-5 repetitions

Safety and Monitoring

All sessions are supervised by trained professionals to monitor form, intensity, and safety. Feedback and Adjustments: Regularly check in with participants to assess their comfort, fatigue levels, and any adverse effects. Adjust the intensity as needed based on individual responses.

Assessment

Cognitive Performance Tests

Backward digit span for working memory and MDS-UPDRS

MRI

To measure creatine levels in the brain and assess neuroprotective effects.

Blood Biomarkers

IGF-1, BDNF, osteocalcin, and oxidative stress markers.

References

• Regulation of cerebral blood flow during exercise, Jordan S Querido, A William Sheel.
• Chapter 9 – Effects of acute high-intensity exercise on cognitive performance in trained individuals: A systematic review, Sarah E. Browne, et al.
• Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial, Caroline Rae, et al

  Creatine supplementation had a significant positive effect on both working memory (backward digit span) and intelligence (Raven’s Advanced Progressive Matrices), both tasks that require speed of processing.

• Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice, Anne-Catherine Passaquin , et al.

  This study found creatine supplementation in mice improves muscle health and may provide a scientific basis for its use as adjuvant therapy in Duchenne muscular dystrophy.

• Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson’s disease mouse model, Yea-Hyun Leem, et al.

  These authors found that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.

• “Heads Up” for Creatine Supplementation and its Potential Applications for Brain Health and Function”, Darren G. Candow, et al.
• Creatine Supplementation, Physical Exercise and Oxidative Stress Markers, Hamid Arazi, et al.

  This review study concluded creatine’s antioxidant mechanisms include reduced ROS and RNS, and that creatine can maintain mitochondrial integrity, increase creatine phosphate (CP) resources, act as a cellular energy buffer, and protect two important cellular targets, mtDNA and RNA, from oxidative damage.

• Effects of Creatine Supplementation on Brain Function and Health, Scott C. Forbes, et al.
• The effects of creatine supplementation on cognitive performance—a randomised controlled study, Julia Fabienne Sandkühler, et al.
• Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity, Piero Sestili, et al.
• The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race, Santos, et al.

Overall health depends on mitochondrial health. Virtually all health conditions from physical and mental performance to cardiovascular health and aging are impacted by mitochondrial health. Optimizing it is therefore a powerful strategy to extend one’s healthspan, or longer quality of life.

Mitochondria are the powerhouse of the cell. They produce and release energy in the citric acid (krebs) cycle and the Electron Transport Chain (ETC).

Mitochondria are essential to cellular function. Cells cannot function without them. Mitochondrial dysfunction is implicated in diabetes, cardiovascular disease, stroke, concussion, and most neurodegenerative diseases. [Chistiakov][Jang]

Measuring Mitochondrial Health

As of 2021, health practitioners can’t test mitochondrial health, so they ignore it.

Commonly performed tests are inadequate. However, changes in overall health can be observed through better tests. Although these better tests don’t provide direct feedback on mitochondrial health, they do provide a more accurate representation of total health than the commonly prescribed, sometimes misleading tests.

Specifically requested performance tests can measure these values through indirect means. Tests such as blood glucose, kidney function, blood pressure, VO₂ max, and cardio IQ can give a rough indication of overall mitochondrial health.

Healthcare Diagnostic Failings

How Doctors Test Your Kidneys

Doctors assess kidney function by glomerular filtration rate (GFR), typically by an eGFR test. eGFR measures blood creatinine — that’s it — and uses fudge factor adjustments that include age, gender, race, and weight, as WebMD officiously explains. They use bodyweight to determine how much muscle you have (WRONG). The thinking behind this is that people have roughly the same ratio of lean body mass to adipose tissue (fat) (WRONG) and, since greater muscle mass leads to greater creatinine levels, heavier people must have more muscle (WRONG). Thus, heavier people with a higher GFR can be expected to be in good health (WRONG).

The eGFR test, which is practically useless for assessing kidney function, is a normal example of healthcare-industry turd-polishing. Be aware of this type of erroneous thinking, established into practice, look out for other such errors, and ask questions and seek answers.

Exercise increases creatinine, a metabolic waste product. And, since exercise increases liver enzymes, increased exercise might also indicate to your doctor that your kidneys and liver are in worse shape — more evidence to him that your new fad health regimen is just more quackery. And, if you’re also taking creatine monohydrate, that will also increase creatinine levels, leading to lower eGFR score, crudely indicating to your assumptive doctor that your kidneys and liver are in worse shape. Your doctor might even tell you to stop taking or doing whatever it is you are doing. Keep in mind, you own your health; your doctor is there to serve you. If you can’t get him to do that, find another doctor.

A better test of kidney function is a Creatinine Clearance test and an albumin/creatinine ratio test. These test circulating creatinine, urinary creatinine, and urinary albumin. Doctors don’t generally request these tests. If you want them, you’ll have to ask for them.

How Doctors Test Your Cardiovascular Health

Low Density Lipoprotein (LDL) particle number assessment is another widespread failing of modern health care. Calculating LDL-C is expensive for widespread screening so, as it is with kidney function, modern healthcare doesn’t test what they find to be “too expensive” and again performs a rough guesstimate.

The alternative to the widespread failure of lipid panel guesstimation is NMR spectronomy particle testing, such as Cardio IQ, which actually measures LDL levels, as well as their size and shape.

Heart disease is the #1 killer in the US, costing an estimated $363 billion dollars per year. That, however, has not stopped the healthcare industry from saving a few bucks by sticking to tradition and avoiding the slightly more expensive NMR tests which have been decreasing in cost over the past thirty years.

Although the best healthcare diagnostics are generally crude, improvements are being made. Get your doctor to work for you. DYOR, find the lab tests you want, communicate with your doctor, and listen to your body.

How Mitochondrial Health and Function can be Improved

On a cellular level, mitochondrial function can be improved in a few ways.

• Mitochondrial biogenesis
• Increased mitochondrial activity
• Mitochondrial strength
• Mitochondrial protection

There are several things you can do to affect those parameters. Understanding of their pathways is key to understanding what, why and how things work.

AMPK and PGC-1 alpha

The AMPK/PGC-1 alpha pathway leads to mitochondrial biogenesis and health.

PGC-1 alpha, the “master regulator” of mitochondrial biogenesis, regulates cellular energy metabolism and induces mitochondrial biogenesis. PGC-1a stands for PPAR Gamma Coactivator-1 alpha. PPAR’s regulate gene expression and PGC 1-a is a PPAR co-activator that regulates cellular energy metabolism. [Liang]

PGC-1 alpha can be activated by a number of things mentioned in this article. Anything that increases PGC-1a increases mitochondrial strength, number, and function.

Anything that increases AMPK increases PGC-1α. [Cantó], though AMPK does more than increase PGC 1-a.

AMPK or AMP-Activated Protein Kinase, is an enzyme that catalyzes the transfer of AMP to ADP to form ATP. ATP is a form of stored energy that is released in the citric acid cycle, forming ADP and AMP. When AMP/ATP or ADP/ATP ratios are too high, AMPK is increased. Increases in AMPK activation and PGC-1a lead to increases in mitochondrial DNA and mitochondrial strength and number.

Lance Hitchins does a deep dive into AMPK

NAD+ — Mitochondrial Fuel

Nicotinamide Adenine Dinucleotide (NAD+) is used in ATP production in the ETC. Think of NAD+ as fuel for mitochondria.

Synergy: Do Everything

Results come from consistent, total application. A halfway applied program leads to partial results. Most people will apply a small fraction of what little they understand and achieve a poor result. Although I explain what to do (exercise, supplements, peptides, etc), it’s up to you to do it consistently. And I’ve explained why and how, so that it can be understood, not followed on blind faith.

Exercise

Physical exercise is the best way to improve mitochondrial health and will have the greatest observable effects on overall health. Exercise should be at the core of any program. Exercise is the best way to increase AMPK.

Exercise increases PGC-1 alpha which stimulates mitochondrial biogenesis. Exercise also causes release of mitochondrial-derived peptides such as MOTS-c, a naturally-produced (more on MOTS-c below). Exercise strengthens mitochondria in all 3 muscle (skeletal, cardiac, and smooth) types, organs like the liver and kidney, and even nervous tissues of the brain. [Park][Steiner]

The most effective type of exercise for improving mitochondrial health is generally agreed to be high-intensity cardiovascular training at or above 75% maximal power (such as high intensity interval training (HIIT)). This is because PGC-1α expression at both the mRNA and protein level increases in an exercise intensity-dependent manner. Supplements, peptides, other approaches to improve performance can raise individual limits of beneficial HIIT. However, a conditioned response to HIIT decreases in benefit after more than 40 repeated bouts. [Bishop][Granata]

Intermittent Fasting

Intermittent Fasting (IF) is fasting between 12 to 24 hours. Several studies have reported significant reductions in body weight and fat mass with no significant changes in lean mass.

Fasting, like exercise, raises PGC-1 alpha. Intermittent fasting (IF) combined with high intensity interval training has synergistic effects suggesting increased mitochondrial mass. [Real-Hohn]

Cold Temperature

Cold exposure strongly induces a release of PGC-1 alpha and, as a result, induces mitochondrial biogenesis. [Chung]

Red Light Therapy, Photobiomodulation (PBM)

The wavelengths 660nm and 850nm increase ATP, increase mitochondrial membrane potential (for the ETC), and improve mitochondrial function in brain, muscle, eye, and organ tissues and, when used pre-workout, reduces post-workout creatine kinase levels. [Silveira][Eells][Keszler][Leal-Junior]

“[Photobiomodulation’s] principal player is the mitochondrion, whether its cytochromes are directly involved as a photoacceptor or indirectly through a vibrational and energetic variation of bound water: water as the photoacceptor.” [Ravera]

Whole body near-infrared (NIR) and IR before exercise increases mitochondrial membrane potential and ATP synthesis with a peak response at 3-6 hours. [Ferraresi]

Follow the instructions recommended by the device manufacturer, usually 20 minutes per day.

Fasted Training Strategy

Sleep early, rise early, do red light therapy for 15–20 minutes, train hard fasted, and then follow with cold or contrast hot/cold showers.

Mitochondrial Peptides Stack

Peptide	Dose
5-Amino-1MQ	50mg daily for two months
Prevents breakdown of NAD+.
MOTS-c	5mg EOD for two to three weeks
Increases PGC-1α expression, attenuates insulin resistance, and enhances glucose metabolism via the AMPK signaling pathway. [Yang]
SS-31	0.5mg / kg bodyweight EOD for two to three weeks
Strengthens the cristae, the structures of the inner mitochondria where the ETC takes place. Reduces free radical production, improves exercise tolerance, and improves diseases stemming from mitochondrial dysfunction. [Campbell][Siegel]

Mitochondrial Supplement Stack

Substance	Dose
NMN	500–1000mg daily
Increases NAD for energy in the electron transport chain (ETC).
PQQ	50–150mg daily
Stimulates mitochondrial biogenesis. Protects against exercise-induced fatigue and oxidative damage by improving mitochondrial function.
CoQ₁₀ Ubiquinol or Phytosome Q10 (Ubiqsome)	300-500mg daily
Generates ATP from metabolic products in the ETC. Protects mitochondria from oxidative damage and dysfunction.
r-ALA	100mg with larger meals
Reduces mitochondrial dysfunction and oxidative damage. Induces mitochondrial biogenesis. Complementarily promotes mitochondrial synthesis with ALCAR. Restores insulin sensitivity in muscle cells. [Shay]
ALCAR	500 – 1000mg pre workout or w/ carbs, 1-2x daily
Nutritively shuttles activated long chain fatty acids into the mitochondria (“carnitine shuttle”). Restores mitochondrial function and increases mtDNA.
Creatine	5-10g daily, w/ carbs
Increases ATP used in the krebs cycle. Prevents mitochondrial damage, increases mtDNA, and induces mitochondrial biogenesis.
Coleus Forskolin	With large meals
Activates cAMP pathway for mitochondrial biogenesis, increased mtDNA, and mitochondrial activity.
Citicoline (CDP Choline)	1000mg prior to exercise
Strengthens mitochondrial membranes. [Rao]

Mitochondrial Peptides Detail

5-Amino-1MQ

5-Amino-1MQ inhibits nicotinamide N-methyltransferase (NNMT). NNMT is an enzyme that breaks down NAD+. Thus, inhibiting NNMT causes an increase in NAD+.

5-Amino-1MQ also activates senescent muscle stem cells, increases muscle recovery, and increase metabolism. [Neelakantan 1]

5-Amino-1MQ inhibits nicotinamide N-methyltransferase (NNMT). NNMT is an enzyme that breaks down NAD+. Thus, inhibiting NNMT causes an increase in NAD+.

5-Amino-1MQ has been shown to activate senescent muscle stem cells, and improve regenerative capacity of aged skeletal muscle, and increase metabolism. [Neelakantan 1][Neelakantan 2] [Neelakantan 1][Neelakantan 2]

MOTS-c

Mitochondrial Open reading frame (ORF) of the twelve S-c (MOTS-c) is a mitochondrially-derived peptide that responds to physical activity. MOTS-c regulates insulin sensitivity, physical capacity and performance.

MOTS-c is a peptide that improves physical function, insulin sensitivity, and metabolic disease states. MOTS-c is produced naturally in humans and is synthesized and sold as a peptide for research purposes.

Exogenous MOTS-c, combined with exercise, synergistically upregulates PGC-1α expression, attenuates insulin resistance, and enhances glucose metabolism via the AMPK signaling pathway. [Yang]

SS-31

SS-31 is a peptide found in the inner membrane of mitochondria, an area where free radicals are produced. SS-31 strengthens the cristae, the structures of the inner mitochondria where the ETC takes place.

Because SS-31 strengthens the inner mitochondria, it reduces free radical production, improves exercise tolerance, and improves diseases stemming from mitochondrial dysfunction. [Campbell][Siegel]

SS-31 restores healthy mitochondrial function, thus, it is primarily of benefit to aged individuals undergoing intense exercise training or those fighting T2D, Parkinson’s, or Alzheimer’s diseases. SS-31 has no effect on young, healthy mitochondria.

In 2021 study out of the University of Washington, researchers found NMN and SS-31 effective at restoring different aspects of mitochondrial and heart health, each through its own respective mechanisms. Combining the two resulted in a synergistic effect that rejuvenated old hearts to the young state. [Whitson]

SS-31 is also an orphaned drug, so, due to government control, it is not readily available for purchase.

These peptides can and should be synergistically complemented and potentiated with supplementation. Exercise is a prerequisite.

Mitochondrial Supplements Detail

Nicotinamide Mononucleotinde (NMN)

Niacin and its metabolite nicotinamide mononucleotinde (NMN) both increase NAD+ and mitochondrial NAD(P)H production under high workload. [Zhang][Whitson]

Niacin causes flushing (from prostaglandin activation) and blunts the release of free fatty acids (FFA). The flushing is uncomfortable but harmless, and reduced FFA release raises HDL. NMN does not have these effects. [Kamanna]

When niacin is metabolized, it uses a methyl group. This can be offset by supplementation of a methyl donor, such as 200–400mg Sam-e, B vitamins, trimethylglycine (betaine), or choline. All of these methyl donors have positive effects. Sam-e, in particular, restores intracellular GSH stores, especially in mitochondria. [Ming]

“Niacin, after undergoing biochemical reactions in the mitochondria with nicotinamide, and tryptophan forms nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin which, when reduced to NAD(H) and NADP(H) respectively, participates in catabolic redox reactions and are cofactors in anabolic redox reactions.” (sic) [Zhang][Whitson]

A 2019 study showed that supplemental NMN reduced levels of creatinine, a metabolic waste product. The mechanism of action is most likely improved kidney function as a direct action of NMN [Weiss]. Because overtraining and creatine supplementation can both raise creatinine levels, NMN is a perfect complement to creatine supplementation or any HIIT exercise regimen.

Pyrroloquinoline quinone (PQQ)

Pyrroloquinoline quinone (PQQ) is a naturally occurring coenzyme manufactured by bacteria, found in plants, and utilized by mammalian cells as an important nutritional growth factor. Because humans do not produce PQQ, this necessary nutrient must be ingested, either from scant amounts found in food, or via supplementation.

PQQ stimulates mitochondrial biogenesis through cAMP response element-binding protein (CREB) phosphorylation and increased PGC-1 alpha expression. [Chowanadisai]

PQQ also protects against exercise-induced fatigue and oxidative damage by improving mitochondrial function. [Liu]

In a 2020 study out of Texas, a small group of untrained men were split into groups. One group got 20mg PQQ per day, the other group got a placebo, and both groups trained on a stationary cycle.

The PQQ group showed greater weight loss and improved mitochondrial biogenesis by way of significant elevations in PGC-1a protein content. Although no advantageous improvement in aerobic exercise performance was found in the PQQ group, the authors attribute this lack of observed aerobic performance to the test itself; that fatigue kicked in before VO₂ max could be realized. Regardless, the weight loss demonstrated that PQQ, even when used alone, has observable effects. [Hwang]

In a 2016 study out of Japan, just 20 mg of BioPQQ™ per day improved cognitive function of elderly subjects. [Itoh]

PQQ was tested with no-observed-adverse-effect-level (NOAEL) at 100 mg/kg bw per day in a 90-day repeated dose oral toxicity study with BioPQQ™. (For a 50kg (110lbs) person, that comes to 5000mg PQQ).

Coenzyme Q10 (CoQ₁₀)

Coenzyme Q10 (CoQ₁₀) is used in the electron transport chain to generate energy in the form of ATP from metabolic products (sugars, fats, and proteins). CoQ₁₀ protects mitochondria from oxidative damage and dysfunction.

CoQ₁₀ administration increases brain mitochondrial concentrations and exerts neuroprotective effects. CoQ₁₀ and PQQ work synergistically with 5-Amino-1MQ to improve neurological function and increase energy turnover. [Matthews][Sarmiento]

Ubiquinol, the reduced form of CoQ₁₀, has shown superior uptake to ubiquinone. Because ubiquinol is fat soluble, it should be taken with fat. [Zhang, Ying]

Phytosome Q10, a lipid-soluble form of CoQ₁₀, has demonstrated higher bioavailability and increased mitochondrial functionality in cultured cells. [Rizzardi

Creatine Monohydrate

Creatine increases power output by increasing ATP. ATP is used a few ways in energy production, including the citric acid cycle and the electron transport chain, both of which occur inside the mitochondria. [Cooper] (See also: How the mitochondria produces ATP in steps.)

Creatine protects mitochondria from damage, increases mitochondrial DNA (mtDNA), and induces mitochondrial biogenesis. This explains why creatine has been evidenced to fight the effects of aging. [Gowayed][Barbieri][Candow]

Coleus Forskolin

Coleus Forskolin activates the cAMP pathway inducing mitochondrial biogenesis, and increasing mtDNA and activity. [Bogacka]

Racemic Alpha-Lipoic Acid (r-ALA)

Alpha-Lipoic Acid (ALA) reduces mitochondrial dysfunction and oxidative damage. ALA protects cells, including neurons, from damage, and induces mitochondrial biogenesis. [Shen][Nutritionreview.org][Fernández-Galilea][Shay]

Sodium r-Lipoate (Na-r-ALA), the Best Form of ALA

Racemic ALA, or r-ALA, is the reduced form of ALA. r-ALA has shown significantly higher absorption than the synthetic S- form (s-ALA). Most commercial formulations use a combination of s- and r- enantiometers because it is cheaper to do so, but do not specify this. [Streeper]

Sodium r-Lipoate (Na-r-ALA) is less prone to polymerization (“gunking up”), is completely soluble in water, and displays much better absorption. [Carlson] Always use Na-r-ALA.

Acetyl L-Carnitine (ALCAR)

Carnitine directly affects mitochondrial respiration. It transfers activated long chain fatty acids into the mitochondria in a series of reactions called the “carnitine shuttle”. [Ferreira]

Carnitine spares glycogen and burns fat during exercise. The form Acetyl L-Carnitine (ALCAR) has the advantage of crossing the blood-brain barrier to reach the brain and improve neurological health and function. [Wall]

References

• [Chistiakov] The role of mitochondrial dysfunction in cardiovascular disease: a brief review
• [Jang] The role of mitochondria in aging
• [Liang] PGC-1 alpha: a key regulator of energy metabolism
• [Cantó] PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure
• [Park] Exercise training improves vascular mitochondrial function
• [Steiner] Exercise training increases mitochondrial biogenesis in the brain
• [Bishop] High-Intensity Exercise and Mitochondrial Biogenesis: Current Controversies and Future Research Directions
• [Granata] Forty high-intensity interval training sessions blunt exercise-induced changes in the nuclear protein content of PGC-1α and p53 in human skeletal muscle
• [Chung] The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue
• [Real-Hohn] The synergism of high-intensity intermittent exercise and every-other-day intermittent fasting regimen on energy metabolism adaptations includes hexokinase activity and mitochondrial efficiency
• [Anton] Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting
• [Silveira] Effects of photobiomodulation on mitochondria of brain, muscle, and C6 astroglioma cells
• [Eells] Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy
• [Keszler] Far red/near infrared light-induced protection against cardiac ischemia and reperfusion injury remains intact under diabetic conditions and is independent of nitric oxide synthase
• [Leal-Junior] Mitochondrial Bioenergetic, Photobiomodulation and Trigeminal Branches Nerve Damage, What’s the Connection? A Review
• [Walden] Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
• [Sarmiento] Coenzyme Q10 Supplementation and Exercise in Healthy Humans: A Systematic Review
• [Ravera] Mitochondrial Bioenergetic, Photobiomodulation and Trigeminal Branches Nerve Damage, What’s the Connection? A Review
• [Ferraresi] Low-level laser (light) therapy increases mitochondrial membrane potential and ATP synthesis in C2C12 myotubes with a peak response at 3-6 hours
• [Neelakantan 1] Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle
• [Neelakantan 2] Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice
• [Yang] MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway
• [Campbell] Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice
• [Siegel] Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice
• [Zhang] Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure
• [Whitson] SS‐31 and NMN: Two paths to improve metabolism and function in aged hearts
• [Kamanna] The mechanism and mitigation of niacin-induced flushing
• [Kamanna] Synergistic protection by S-adenosylmethionine with vitamins C and E on liver injury induced by thioacetamide in rats
• [Matthews] Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects
• [Zhang, Ying] Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects
• [Rizzardi] Coenzyme Q10 Phytosome Formulation Improves CoQ10 Bioavailability and Mitochondrial Functionality in Cultured Cells
• [Chowanadisai] Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression
• [Liu] Pyrroloquinoline quinone protects against exercise-induced fatigue and oxidative damage via improving mitochondrial function in mice
• [Hwang] Effects of Pyrroloquinoline Quinone (PQQ) Supplementation on Aerobic Exercise Performance and Indices of Mitochondrial Biogenesis in Untrained Men
• [Itoh] Effect of the Antioxidant Supplement Pyrroloquinoline Quinone Disodium Salt (BioPQQ™) on Cognitive Functions
• [Shay] Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
• [Streeper] Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle
• [Carlson] The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects
• [Ferreira] Chronic oral ingestion of l-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans
• [Wall] L-Carnitine and acetyl-L-carnitine roles and neuroprotection in developing brain
• [Bogacka] Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro
• [Irie]Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide¥ metabolite levels in healthy Japanese men
• [Weiss]Study Indicates NMN Has Anti-Aging Potential for Kidneys
• [Shen] R-alpha-lipoic acid and acetyl-L-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes
• [NutritionReview.org] (R)-Lipoic Acid: Unique ‘Mitochondrial Antioxidant’ Fights Premature Aging
• [Fernández-Galilea] α-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects
• [Barbieri] Creatine Prevents the Structural and Functional Damage to Mitochondria in Myogenic, Oxidatively Stressed C2C12 Cells and Restores Their Differentiation Capacity
• [Gowayed] Enhanced mitochondrial biogenesis is associated with the ameliorative action of creatine supplementation in rat soleus and cardiac muscles
• [Cooper] Creatine supplementation with specific view to exercise/sports performance: an update
• [Candow] Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation
• [Rao] Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection

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Good preventative measures for preventing and treating SARS-CoV-2 include raw ginger (which is antiviral), other vanilloids (capsaicin), rigorous hygiene, regular exercise, optimal vitamin D levels, optimal hGH levels, berberine, ivermectin, vasoactive intestinal peptide (VIP) (and having standard injection supplies (sterile syringes, needles, bacteriostatic water, prep swabs, alcohol, etc.) on hand, to administer it at home).

Individual health varies and so do measures to treat it. One-size-fits-all solutions, such as with anything from the government, usually fail in specific cases and always fall short of the ideal. Not everything in this article applies to all persons, some of it will apply to most persons, some will apply to few.

Rest & Recovery

Sleep and the circadian system exert a strong regulatory influence on immune functions. Sufficient, regular sleep is essential. Optimize sleep.

Sleep and immune function.

Lung Health and Breathing

The worst cases of COVID-19 are those with lung damage. This is caused by excessive inflammation as a response of the immune system. Breathing exercises, in addition food and medicine, can improve lung condition.

Pulmonary rehabilitation is exercise training and breathing techniques for people suffering from respiratory conditions.

Pulmonary rehabilitation is a feasible, safe and effective therapeutic option in COVID-19 patients independent of disease severity.

See also: Benefits of pulmonary rehabilitation in COVID-19: a prospective observational cohort study.

Cleanliness & Personal Hygiene 

SARS-CoV-2 accumulates in the nasopharyngeal area. The viral load can be reduced by physical washing with fresh ginger or iodine by gargling and neti pot.

For oral hygeine, use a tongue scraper, brush inside the mouth, gargle and use a water flosser.

It is important to clean all areas of the body, nose, ears, throat, and anal/rectal area.

The Claim: Gargling With Salt Water Can Ease Cold Symptoms (New York Times)

In a randomized study published in The American Journal of Preventive Medicine in 2005, researchers recruited almost 400 healthy volunteers and followed them for 60 days during cold and flu season. Some of the subjects were told to gargle three times a day. At the end of the study period, the group that regularly gargled had a nearly 40 percent decrease in upper respiratory tract infections compared with the control group, and when they did get sick, “gargling tended to attenuate bronchial symptoms,” the researchers wrote.

2. Nasal and sinus

Use a neti pot or, if you don’t have one, pour salt water in one nostril until it comes out the other side.

Saline Nasal Irrigation for Upper Respiratory Conditions
SNI may be effective adjunctive treatment for mild-to-moderate allergic rhinitis, rhinitis of pregnancy and viral URIs.

An article published in the journal Lung India stated:

“hypertonic saline gargles and nasal wash may work in preventing the disease and may also be useful in reducing nasopharyngeal viral load to provide symptomatic relief. Further, it may reduce viral shedding and reduce the transmission of the illness. This may break the chain of infection. COVID 19 disease is mild in eighty percent of patients and resolves spontaneously. Therefore, nasopharyngeal wash may be useful especially in subgroup of the population at high risk such as subjects with comorbid conditions and above 60 years of age.”

While this is not hard evidence to strongly conclude anything about the effects of neti pot usage, it provides reasonable scientific explanation of how it would helpful. It is a low cost treatment with no adverse side effects.

Exercise

Moderate-intensity exercise protects against respiratory viral infection. Overtraining reduces immune function.

See also: Exercise and the immune system

Photobiomodulation

Photobiomodulation with red and near infrared light has been scientifically shown to significantly decrease pulmonary swelling, neutrophil influx, and generation of pro-inflammatory cytokines.

See also:

Probable positive effects of the photobiomodulation as an adjunctive treatment in COVID-19: A systematic review

Fresh, but not dried, ginger dose-dependently inhibited viral attachment of human respiratory syncytial virus to human upper and lower respiratory tract. 

Fresh ginger extract can be prepared by grating the fresh ginger rhizome with a small-holes cheese grater and repeatedly squeezed and soaking it in water for further extraction, and filtering it to separate the pulp. The fresh ginger extract can be mixed with honey and warm water or juices, such as apple or cherry, if desired.

An Indian analytical study published in Future Journal of Pharmaceutical Sciences (FJPS) found ginger (Z. officinale), used as a viral purge, indicated good potential in reducing viral load and shedding of SARS-CoV-2 in the nasal passages. (See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794642/)

Vanilloids such as capsaicin desensitize the TRPV1 receptor.

The TRPV1 receptor is responsible for the overexpression of inflammation in respiratory infections.

Administration of capsaicin is proven to desensitize the TRPV1 receptor leading to reduced overreaction to respiratory infection.

A paper published in Medical Drug Discovery found:—

This most recently published review ( https://doi.org/10.1016/j.medidd.2020.100033 ) looks at the tantalizing possibility of TRPV1 (The transient receptor potential cation channel subfamily V member 1, also known as the capsaicin receptor or the vanilloid receptor 1) playing a substantial role in the prognosis of viral infections and in particular with COVID-19. Preclinical data suggest, and the authors posit, that COVID-19 pulmonary changes are linked to a strong immune response and an inability to ablate or dampen the immune response. Available data also indicate that inhibition of afferent activity in particular removal of TRPV1+ afferent fibers from the lung and airways can have a beneficial action on the compromised lung function and clearance of infection. Moreover, inactivation of the TRPV1+ innervation could also be “beneficial for the prevention or treatment of ventilator-associated lung injury”.

Standing out from the crowd in treating COVID-19

The Global Allergy and Asthma European Network (GA2LEN) studies comorbidities and etiology of asthma. In seemingly informal testing, they found “Oral capsaicin induces a very fast improvement in COVID-19 symptoms suggesting TRPV1 channel desensitization”.

Capsaicin and ginger are TRPV1 agonists (this is scientifically established).

See also:

In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2

Funfact: Birds, Capsaicin, and Olfactory VR’s

Aside: the olfactory sense in birds (modern avian dinosaurs) detects capsaicin in the chili peppers. The birds smell them, eat them, poop out the seeds, and propagate the chili peppers. Digestive enzymes of the birds can scarify seeds and have of positive beneficial effect on their survivability and propagation.

Unlike mammals, these modern avian dinosaurs don’t perceive capsaicin as painful. (See: Molecular Basis for Species-Specific Sensitivity to “Hot” Chili Peppers)

Berberine

Berberine is an alkaloid found in several plants. It is available in supplement form over the counter.

A Polish study, “Antiviral Activity of Berberine“, found,

“Many viruses can target the MAPK pathway to manipulate cellular functions and control viral replication, leading to host cell death. These pathways are also involved in inhibitory effect of BBR. In addition, BBR can inhibit inflammatory responses triggered by viruses.”

Antiviral activity of berberine

A 2021 study examined the effects of Berberine on SARS-CoV-2 found,

In conclusion, our study puts forth two small molecule compounds, BBR and OLX, as repurposed antiviral molecules against SARS-CoV-2, in doses lower than that previously shown to be safe in human clinical trials. While OLX is effective at early steps of the viral life cycle, likely interfering with entry processes, BBR acts on the later stages and it likely reduces the infectivity of newly produced virions. BBR and OLX are effective in a physiologically relevant cell culture model at low micromolar concentrations and it could be considered for further assessment.

Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro

Another 2021 study, this one out of China, titled “Berberine reduces circulating inflammatory mediators in patients with severe COVID-19.” found,

berberine exhibits direct anti-influenza virus effects in vitro, inhibits lung inflammatory injury, and reduces the release of oxygen radicals in mice suffering from pneumonia associated with influenza virus. 

Berberine reduces circulating inflammatory mediators in patients with severe COVID-19.

Berberine also lowers blood sugar. Berberine’s cytotoxic effects make it useful to fight cancer.

Ivermectin

Ivermectin is evidently an effective treatment and prophylactic. Especially if you want to protect front line healthcare workers or anyone who has likely come in to close contact with infected persons.

“Two-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month.”

Recommended dose of Ivermectin for adults is 0.2 mg/kg orally, per day. (See: https://www.drugs.com/dosage/ivermectin.html)

https://covid19criticalcare.com/guide-for-this-website/how-to-get-ivermectin/

1. Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study
2. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness
3. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study

Vasoactive Intestinal Peptide

Vasoactive Intestinal Peptide (VIP) is an effective treatment for critical COVID-19 cases with comorbidities. VIP blocks replication of the SARS-CoV-2 virus, inhibits cytokine synthesis, and upregulates surfactant production in human pulmonary cells.

Participants received 3 successive 12-hour intravenous infusions of VIP at 50, 100, and 150 pmol/kg/hr.

Setting up an IV infusion is more complicated than IV injections.

See also:

1. Vasoactive Intestinal Peptide Promising Treatment for COVID-19 Respiratory Failure
2. Effectiveness of ZYESAMI™ (Aviptadil) in accelerating recovery and shortening hospitalization in critically-ill patients with COVID-19 Respiratory Failure: interim report from a phase 2b/3 multicenter trial

Growth Hormone

Human growth hormone (hGH) stimulates thymic release of lymphocytes, increases antibody and T cell production, and reduces inflammatory cytokines.

Growth hormone (GH) secretagogues such as Tesamorelin and CJC-1295 can be used to optimize GH levels.

See:

1. Trade off situation between thymus and growth hormone: age-related decline of growth hormone is a cause of thymic involution but favorable for elongation of lifespan
2. Immune Enhancing Effect of a Growth Hormone Secretagogue

Growth hormone can affect development, so it should only be used by adults. Older persons who have lower levels of GH may find increased benefit from a short course of a GH secretagogue.

Fermented Foods

A 2021 European regional study headed by Jean Bousquet proposed that fermented cabbage prevents the severity of COVID-19. The authors postulate many possible reasons for the regionally-observed effects, as they pertain to their area of focus, fermented cabbage.

Fermented foods inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression nuclear factor kappa-light-chain-enhancer of activated B cells NFK2 activation, citing sulforaphane, a component also found in broccoli and garlic, as a strong NFK2 inhibitor.

Bousquet, in another multi-university study, Spices to Control COVID-19 Symptoms: Yes, but Not Only… concludes that fermented foods are agonists of NRF2:—

Fermented vegetables and spices are agonists of the antioxidant transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and spices are transient receptor potential ankyrin 1 and vanillin 1 (TRPA1/V1) agonists. These mechanisms may explain many COVID-19 symptoms and severity. It appears that there is a synergy between Nrf2 and TRPA1/V1 foods that may explain the role of diet in COVID-19. One of the mechanisms of COVID-19 appears to be an oxygen species (ROS)-mediated process in synergy with TRP channels, modulated by Nrf2 pathways. Spicy foods are likely to desensitize TRP channels and act in synergy with exogenous antioxidants that activate the Nrf2 pathway.

Spices to Control COVID-19 Symptoms: Yes, but Not Only…

Mitochondrial peptides (5-Amino-1MQ, SS-31, and MOTS-c, et al), work in essentially two ways. They either increase mitochondrial function and activity, increase the number of mitochondria in the cell, or both.

SS-31 is a peptide found “in the inner membrane of mitochondria,, an area where free radicals are produced. Animals studies have shown that SS-31 reduces free radical production and decreases oxidative stress, improving diseases stemming from mitochondria dysfunction.” SS-31 is also an orphaned drug, so due to patent status, it is not readily available for use.

These peptides can be synergized by supplementation with CoQ10, PQQ, and Forskolin to increase mitochondrial biogenesis and activity.

Photobiomodulation with 660 and 850nm wavelengths can improve mitochondrial function in brain, muscle, and organ tissues. [5]

• CoQ10, and PQQ may work synergistically with 5 amino 1mq to improve neurological function and increase energy turnover.[1][2]
• PQQ Pyrroloquinoline Quinone works synergistically stimulate Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression.[3]
• Forskolin increases the number of mitochondria and their activity.[4]

Creatine may be used to increase power output by an increase ATP, another metabolic product that is the result of the citric acid cycle which takes place in the mitochondria.[7]

Niacin and its derivative NMN may also be used synergistically increase mitochondrial NAD(P)H production under higher workload.[8][9]

“Although NMN and SS‐31 both target mitochondria, they do so via different mechanisms of action. Thus, we hypothesized that the drugs would differ in effect on the heart and may have a synergistic effect when applied together. We sought to compare and contrast the mechanism and effects of these drugs in order to better understand each individually and how age‐related deficits in heart function can be addressed.”

“Niacin, after undergoing biochemical reactions in the mitochondria with nicotinamide, and tryptophan forms nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin which, when reduced to NAD(H) and NADP(H) respectively, participates in catabolic redox reactions and are cofactors in anabolic redox reactions.” [8][9]

When niacin is metabolized, it uses a methyl group. This can be offset by supplementation of 200–400mg Sam-e, a methyl donor. Sam-e also restores intracellular GSH stores, especially in mitochondria.[10]

[1] Coenzyme Q10 Supplementation and Exercise in Healthy Humans: A Systematic Review
[2] Coenzyme Q₁₀ administration increases brain mitochondrial concentrations and exerts neuroprotective effects
[3] Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression
[4] Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro
[5] Effects of photobiomodulation on mitochondria of brain, muscle, and C6 astroglioma cells
[6] Far red/near infrared light-induced protection against cardiac ischemia and reperfusion injury remains intact under diabetic conditions and is independent of nitric oxide synthase
[7] Creatine supplementation with specific view to exercise/sports performance: an update
[8] Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure
[9] SS‐31 and NMN: Two paths to improve metabolism and function in aged hearts
[10] Synergistic protection by S-adenosylmethionine with vitamins C and E on liver injury induced by thioacetamide in rats